Zhifeng Qiu

HIV infection: an independent risk factor of peripheral arterial disease.

To the Editors: Highly active antiretroviral therapy (HAART) had significantly reduced the death rate resulted from HIV infection. However, HAART had also increased the risk of coronary heart disease in HIVinfected patients, especially in those on protease inhibitors (PIs). Whether HIV infection itself can promote the atherosclerosis is still controversial. Ankle brachial index (ABI) has been validated against lower extremity contrast angiography to determine its sensitivity, specificity, and accuracy as a diagnostic tool for lower extremity peripheral arterial disease, and the presence of a low ABI was predictive of total and cardiovascular mortality. Pulse wave velocity (PWV) is noninvasive parameter directly proportional to arterial wall stiffness. Our study aimed to determine whether the HIVinfected patients with or without receiving HAART are more likely to develop atherosclerosis in comparison to the general population, using ABI and PWV; and to assess the associated factors of peripheral arterial atherosclerosis. Our study had been approved by Peking Union Medical College Hospital Institutional Review Board. Eighty-two patients with HIV infection were divided into 2 groups: antiretroviral therapy (ART) na€ıve group comprising 41 antiretroviral-naive patients and HAARTtreated group comprising 41 patients on HAART for more than 12 months (34.76 17.1 months). Forty-three healthy people whose HIV screen tests were negative were enrolled as control subjects. Total cholesterol, triglyceride, lowdensity lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were determined by standard methods using Olympus AU5400 chemistry autoanalyzer (Olympus, Tokyo, Japan). CD4 lymphocyte count and CD8 lymphocyte count were measured by Epics XL flow cytometry (Beckman Coulter, Ramsey, MN). Plasma HIV RNA level was determined using a branched DNA assay (lower limit of quantification, 50 copies RNA/mL, version 3.0; Bayer Health Care, Leverkusen, Germany). ABI and PWV were determined using a pulse pressure analyzer (model BP-203RPE II; Nihon Colin, Komaki, Japan). The ABI was performed by measuring the systolic blood pressure from both brachial arteries and from both posterior tibial arteries; ABI was then calculated by the device as the ratio of systolic blood pressure in the leg to that in the arm on each side, and the average value was used for analysis. Pulse waves were recorded using sensors placed on both posterior tibial arteries. The time intervals required for the pulse waves to travel from the heart to both posterior tibial arteries were measured, and the distances between the heart and both posterior tibial arteries were estimated from the patient’s height. The PWV was calculated by dividing the distance by the time interval. For statistical analysis, between-group differences were compared by 2-sample t tests or Mann– Whitney tests (non-normal distribution) for continuous variables and by x analysis for categorical variables. Correlation was tested with Spearman rank order or Pearson correlation coefficient. Multiple linear regression analysis was used to test for independent associations between ABI and various factors. No significant statistical differences were observed among 3 groups considering age, sex, and family history of coronary heart disease or current smoking (Table 1). The ART-naive patients were more likely to be hypertensive and had lower level of total cholesterol and LDL-C than control subjects (P < 0.01). A lower HDL-C level was also noted in our ART-naive patients (P < 0.01). ART na€ıve HIV-infected patients have a lower ABI (P < 0.001) and a higher PWV (P = 0.010) when compared with control subjects. We included 41 ART-naive patients and 43 control subjects in a single group for linear regression analysis (R = 0.362; P = 0.001). We found that factors associated with reduced ABI were age (B = 0.03; 95% confidence interval: 0.000–0.005; P = 0.039) and HIV infection (B = 0.069; 95% confidence interval: 0.120 to 0.017; P = 0.01). That meant, after adjustment for other cardiovascular risk factors, HIV infection group was associated with a 0.069 lower ABI compared with control subjects. However, Pearson relation analysis shows not any association between ABI and common HIV infection parameters [CD4 lymphocyte count (r = 0.161; P = 0.314), CD8 lymphocyte count (r = 0.026; P = 0.871), CD4/CD8 ratio (r = 0.055; P = 0.731), and HIV RNA (r = 0.047; P = 0.770)] in patients with HIV. Patients in HAART-treated group mostly were treated with nonnucleoside reverse transcriptase inhibitors (NNRTIs, 40 of 41, 98%) and nucleoside reverse transcriptase inhibitors (NRTIs, 41 of 41, 100%). Only 7.3% (3 of 41) of the patients were on PIs–containing regimen. There were no differences in total cholesterol, triglyceride, LDL-C, HDL-C, and ABI between HAART-treated group and ART-naive group. Compared with ART-naive patients, the HAART-treated patients showed a lower body mass index, blood pressure, and PWV, as well as the HIV RNA level (P < 0.05). The idea that HIV-infected patients are likely to have an atherogenic lipid profile, such as high levels of total cholesterol, LDL-C, and triglyceride, has been reported by several studies. HAART is thought to be associated with these metabolic abnormalities. However, our ART-naive patients had lower total cholesterol and LDL-C levels, which is an atheroprotective lipid profile. This result supports the assumption that HAART may be contributory to dyslipidemia in HIV-infected patients. In this study, we proved that ART-naive patients have lower ABI compared with HIVuninfected control subjects, suggesting that HIV-infected patients are more likely to develop peripheral arterial disease. We also found in ART-naive HIV-infected patients having higher PWV level, which is also a marker of Supported by National Key Technologies R&D Program for the 11th Five-year Plan (2008ZX10001-006), Ministry of Health Clinical HIV/AIDS Research Grant (2007–2009), and Beijing Science and Technology Program Fund (D0906003040491).

Long-Term Persistence of Robust Antibody and Cytotoxic T Cell Responses in Recovered Patients Infected with SARS Coronavirus

Most of the individuals infected with SARS coronavirus (SARS-CoV) spontaneously recovered without clinical intervention. However, the immunological correlates associated with patients recovery are currently unknown. In this report, we have sequentially monitored 30 recovered patients over a two-year period to characterize temporal changes in SARS-CoV-specific antibody responses as well as cytotoxic T cell (CTL) responses. We have found persistence of robust antibody and CTL responses in all of the study subjects throughout the study period, with a moderate decline one year after the onset of symptoms. We have also identified two potential major CTL epitopes in N proteins based on ELISPOT analysis of pooled peptides. However, despite the potent immune responses and clinical recovery, peripheral lymphocyte counts in the recovered patients have not yet been restored to normal levels. In summary, our study has, for the first time, characterized the temporal and dynamic changes of humoral and CTL responses in the natural history of SARS-recovered individuals, and strongly supports the notion that high and sustainable levels of immune responses correlate strongly with the disease outcome. Our findings have direct implications for future design and development of effective therapeutic agents and vaccines against SARS-CoV infection.

Correlation between gag-specific CD8 T-cell responses, viral load, and CD4 count in HIV-1 infection is dependent on disease status.

Background: It still remains controversial which kind of relationships exist between HIV-1-specific CD8 T-cell responses and HIV RNA load or CD4 count over the course of the infection. This study was designed to investigate the role of HIV-specific CD8 responses in patients with different disease status. Methods: Three cohorts of patients were selected according to CD4 count levels: long-term nonprogressors (LTNPs, n = 19), asymptomatic progressors (CD4 counts between 500 and 350 cells/mm3, n = 14), and progressors (CD4 counts <350 cells/mm3, n = 23). Six of the LTNPs experiencing a quick loss of CD4 T-cells and another 6 LTNPs with stable CD4 counts were followed up. T-cell responses were studied using interferon (IFN) &ggr;-ELISpot assay against HIV p24 and 11 pools of HIV-Gag peptides. Results: No significant differences were found in Gag-specific CD8 responses among the 3 cohorts. However, inverse correlations were identified between CD8 responses and CD4 counts in asymptomatic progressors and between CD4 responses and viral loads in progressors. In addition, the sequential dynamics of CD8 responses in 6 LTNPs showed that with a quick loss of CD4 T-cells around the range of 500 to 300 cells/mm3, more vigorous CD8 responses were induced simultaneously, and plasma viremia was still kept relatively stable. Conclusions: These data suggest that the relationship between CD8 response and viral load or CD4 count is not universally consistent throughout the entire course of HIV-1 infection. Gag-specific CD8 responses may play differential roles in different stages of HIV-1 infection, and the maintenance of a threshold level of CD4 T-cells may contribute to mediate effective HIV-specific responses in natural control of HIV-1 infection.

Reference ranges and age-related changes of peripheral blood lymphocyte subsets in Chinese healthy adults

This study was performed to build region-specific reference ranges of peripheral blood lymphocyte subsets for Chinese healthy adults from the young to the elderly and analyze the trends of changes in lymphocyte subsets for evaluating the impact of age on the values. 151 healthy adults aged 19–86 were recruited based on the SENIEUR protocol. Three sets of reference ranges were finally built applicable for the healthy young (19–44 years), middle-aged (45–64 years) and elder adults (⩾65). Comparisons in parameters among the three cohorts showed that a statistically significant increase in CD16CD56+ NK cell was observed between the middle-aged and elder cohorts, whereas for the majority of the parameters, a significant decline was observed between the young and the middle-aged cohorts. Further results showed that inverse correlations were observed between the age and CD19+ B, CD3+ T, CD3+CD4+ T, CD4+CD45RA+CD62L+ naïve T cell and CD4+CD28+/CD4+, while the positive one was identified between the age and the NK cell. These significant changes of the most of immune parameters provided evidence for immunosenescence. Notably, T cell activation markers of CD8+CD38+ and CD8+HLA-DR+ showed reverse trends of association with age, which provides a clue for further researches on the mechanisms underlying the paradoxical clinical presentation of the elder patients.

Accelerating effect of human leukocyte antigen-Bw6 homozygosity on disease progression in Chinese HIV-1-infected patients.

Most HIV-1-infected individuals progress to AIDS within 8 to 10 years after seroconversion. Less than 5% of them, however, remain asymptomatic, although their CD4+ T-cell counts stay normal. In this study, our polymerase chain reaction sequence-specified primer (PCR-SSP) based human leukocyte antigen (HLA)-B genotyping of 28 typical progressors (TPs) and 15 long-term nonprogressors (LTNPs) revealed some evidence that an HLA-B locus polymorphism can influence the rate of disease progression in Chinese HIV-1-infected individuals: 12 of 28 TPs (43%) were HLA-Bw6 homozygotes. Only 1 of 15 LTNPs (6.7%) was homozygous for the polymorphism (P = 0.013), suggesting that HLA-Bw6 homozygosity is associated with accelerated disease progression. In contrast, 3 of 15 LTNPs (20%) were HLA-Bw4 homozygotes, whereas none of the 28 TPs were homozygotes (P = 0.037), supporting the conclusion that HLA-Bw4 homozygosity may have a protective role. Interestingly, the frequency of the HLA-B*15 allele was extremely high in the TP group (23.2%), which may be associated with faster disease progression in Chinese patients.

Prevalence of hepatitis B and C viruses in HIV-positive patients in China: a cross-sectional study.

Liver disease related to hepatitis B (HBV) and hepatitis C (HCV) may temper the success of antiretroviral therapy (ART) in China. Limited data exist on their prevalence in HIV‐positive Chinese. A multi‐centre, cross‐sectional study was carried out to determine the prevalence and disease characteristics of HBV and HCV co‐infection in HIV‐positive patients across 12 provinces.

Combination Antiretroviral Therapy Is Associated With Reduction in Liver Fibrosis Scores in HIV-1-Infected Subjects.

Abstract HIV increases the risk of liver disease as do two common coinfections, hepatitis B and C viruses (HBV and HCV). However, whether combination antiretroviral therapy (cART) reverses or exacerbates hepatic fibrosis remains unclear. This was an observational retrospective study. cART-naïve HIV-infected subjects without a history of substance abuse (including alcohol) had liver disease stage determined by aspartate aminotransferase-to-platelet ratio indices (APRIs) and fibrosis-4 (FIB-4) before and 24 and 48 weeks after cART. All the data were retrieved from previously established cohorts. Values before and after cART were compared using Wilcoxon test for paired samples. Regression analyses were used to determine factors associated with moderate-to-severe liver disease. Of the 1105 HIV-infected subjects, 120 were HBV coinfected and 64 were HCV coinfected. About 20% of HIV monoinfected participants had APRI and FIB-4 scores consistent with moderate-to-significant fibrosis compared to ∼36% of HIV–HBV coinfected and 67% to 77% of HIV–HCV coinfected participants. In adjusted analyses compared with HIV monoinfection, HBV coinfection was associated with 1.18-fold higher APRI (Pu200a<u200a0.001) and a 1.12-fold higher FIB-4 (Pu200a=u200a0.007) prior to cART; while HCV coinfection was associated with 1.94-fold higher APRI (Pu200a<u200a0.001) and a 1.43-fold higher FIB-4 (Pu200a<u200a0.001). After 48 weeks of cART, both fibrosis scores decreased in all subjects; however, HCV coinfection was still associated with higher fibrosis scores at week 48 compared to HIV monoinfection. cART was associated with improvement in hepatic fibrosis scores in the majority of HIV-hepatitis coinfected and HIV-monoinfected Chinese participants.

The interaction of CD4 T-cell count and nevirapine hepatotoxicity in China: A change in national treatment guidelines may be warranted

Objectives:Nevirapine (NVP), a still widely used nonnucleoside reverse transcriptase inhibitor, can cause severe hepatotoxicity. Previous studies suggest that CD4 cell counts more than 250 cells per microliter in women and more than 400 cells per microliter in men are risk factors for NVP-related hepatotoxicity. These studies have informed Chinese national treatment guidelines. We evaluate whether current Chinese guidelines for NVP use are appropriate. Methods:Longitudinal data were pooled from 2 clinical trials between 2005 and 2009 across mainland China. Five hundred sixty-six antiretroviral therapy–naive Chinese patients were given NVP-containing antiretroviral therapy for 24 weeks. Hepatotoxicity was defined as alanine aminotransferase, aspartate transaminase, or total bilirubin level greater than 1.25 times the upper limit of normal range. Severe hepatotoxicity was defined as greater than 5 times the upper limit of normal range. Results:One hundred ninety-seven (36.1%) patients developed hepatotoxicity during treatment, including 42 (7.7%) patients with severe hepatotoxicity. CD4 cell count more than 250 cells per microliter was an independent predictor for hepatotoxicity both in men [relative risk = 1.22 (95% confidence interval: 1.04 to 1.44)] and in women [relative risk = 1.72 (95% confidence interval: 1.20 to 2.46)]. Severe hepatotoxicity was also more common among all persons with CD4 >250 cells per microliter. Conclusions:Hepatotoxicity was a common adverse effect of NVP among men and women with CD4 >250 cells per microliter. Chinese treatment guidelines should be considered to reflect this risk.

Multicenter cohort study of diabetes mellitus and impaired fasting glucose in HIV-infected patients in China.

Background:As life expectancy increases, HIV-infected patients are facing a wide array of metabolic complications, including diabetes mellitus (DM) and impaired fasting glucose (IFG). However, little is known about the incidence of and risk factors for glycemic disorders in Chinese HIV-infected patients. Methods:Longitudinal data were pooled from a multicenter clinical trial of combination antiretroviral regimens between 2009 and 2010 across Mainland China. DM was defined as fasting glucose level ≥7.0 mmol/L and IFG as between 5.6 and 6.9 mmol/L on 2 separate measurements. We calculated the incidence densities of DM and IFG. Risk factors for DM and IFG were also identified. Results:Four hundred fifteen patients contributed 457.35 person-years of follow-up. The incidence densities of DM and IFG were 2.62 and 35.64 per 100 person-years, respectively. In a multivariate analysis, advanced age [adjusted hazard ratio (HR): 1.03, 95% confidence interval (CI): 1.01 to 1.04], hepatitis B virus coinfection (adjusted HR: 1.59, 95% CI: 1.06 to 2.38), and baseline fasting glucose (adjusted HR: 1.28, 95% CI: 1.00 to 1.63) were associated with DM and IFG. Conclusions:A high incidence of DM and IFG was detected in Chinese HIV-infected patients receiving combination antiretroviral therapy. Clinicians should be aware of the potential for an increased risk of glycemic disorders in Chinese HIV-infected patients, particularly those of advanced age, with hepatitis B virus coinfection or high baseline fasting glucose.

Association Between Gut Microbiota and CD4 Recovery in HIV-1 Infected Patients

Composition of the gut microbiota has been linked with human immunedeficiency virus (HIV)-infected patients on antiretroviral therapy (ART). Evidence suggests that ART-treated patients with poor CD4+ T-cell recovery have higher levels of microbial translocation and immune activation. However, the association of the gut microbiota and immune recovery remains unclear. We performed a cross-sectional study on 30 healthy controls (HC) and 61 HIV-infected individuals, including 15 immunological ART responders (IRs), 20 immunological ART non-responders (INRs) and 26 untreated individuals (VU). IR and INR groups were classified by CD4+ T-cell counts of ≥350 cells/mm3 and <350 cells/mm3 after 2 years of ART, respectively. Each subject’s gut microbiota composition was analyzed by metagenomics sequencing. Levels of CD4+ T cells, CD8+HLA-DR+ T cells and CD8+CD38+ T cells were measured by flow cytometry. We identified more Prevotella and fewer Bacteroides in HIV-infected individuals than in HC. Patients in INR group were enriched with Faecalibacterium prausnitzii, unclassified Subdoligranulum sp. and Coprococcus comes when compared with those in IR group. F. prausnitzii and unclassified Subdoligranulum sp. were overrepresented in individuals in VU group with CD4+ T-cell counts <350 cells/mm3. Moreover, we found that the relative abundance of unclassified Subdoligranulum sp. and C. comes were positively correlated with CD8+HLA-DR+ T-cell count and CD8+HLA-DR+/CD8+ percentage. Our study has shown that gut microbiota changes were associated with CD4+ T-cell counts and immune activation in HIV-infected subjects. Interventions to reverse gut dysbiosis and inhibit immune activation could be a new strategy for improving immune reconstitution of HIV-1-infected individuals.